Patients with Schizophrenia, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, depression and various other neurological/neurodegenerative diseases frequently suffer from behavioral and cognitive impairments resulting in debilitating disruption to their daily lives. Over the years many pharmacological treatments have been discovered that provide some improvement in behavior and cognitive function. However, the improvement is modest at best, and as is often the case, the underlying dose-limiting adverse effects associated with these treatments, including extrapyramidal and metabolic side-effects, lead to partial responsiveness, and non-compliance.
In an effort to discover new and improved pharmacological treatments, researchers began to look at the muscarinic acetylcholine receptor (mAChR) as a viable mechanism. There are five mAChRs subtypes (M1-M5) that have been identified and are part of the G protein-coupled receptor (GPCR) superfamily. These subtypes are distributed widely throughout the periphery and the central nervous system, with the M1 and M4 subtypes being predominantly expressed in the CNS.
Researchers have since focused on identifying subtype selective M4 muscarinic acetylcholine receptor activators. For example, positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor have gained attention as a further method of treating the behavioral impairments associated with schizophrenia and other neuropsychiatric disorders, e.g., Alzheimer's Disease. [See: Bubser, Michael, et al., “Selective Activation of M4 Muscarinic Acetylcholine Receptors reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents”, American Chemical Society, Chemical Neuroscience (2014); and Bynum, Nellie E., et al., “Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100”, Neuropsychopharmacology (2014) 1-16]. While the etiology of schizophrenia is unclear, it is believed that an imbalance in the dopaminergic system plays a major role. mAChR receptors are known for their regulation of dopamine levels in critical regions of the brain involved with psychosis, with M4 being the primary subtype for dopamine regulation. (See: Chan, W. Y., et al., “Allosteric Modulation of the Muscarinic M4 receptor as an Approach to Treating Schizophrenia”, PNAS, August 2008, Vol. 105 No. 31 p. 10978; and Byun, Nellie, et al., “Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100”, Neuropsychopharmacology (2014) 1-16). Another hypothesis for M4 in schizophrenia is its ability to affect hippocampal circuitry (Shirley, Jana K., et al., An allosteric potentiator of M4 mACHR modulates hippocampal synaptic transmission”, Nature Chemical Biology, Vol. 4, No. 1, January 2008; and Dasari, Sameera, et. al., “M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons”, J. Neurophysiology 105: 779-792, 2011) through modulation of the hippocampal trisynaptic pathway which has been reported to be disregulated in Schizophrenic (Tamminga, Carol A., et. al., “Glutamate Dysfunction in Hippocampus: Relevance of Dentate Gyrus and CA3 Signaling”, Schizophrenia Bulletin Vol. 38, no. 5, pp. 927-935, 2012), Alzheimer's Disease (Quiroz et al 2010 Ann Neurol, Filipini et al 2009 PNAS) and aMCI patients (Bakker, A., et. al., “Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance”, Neuromalge: Clinical 7 (2015) 688-698). Hyperactivity in the hippocampal trisynaptic pathway has been proposed as a likely cause for psychosis in schizophrenics (Tamminga, et al.).
Vanderbilt University has published several International Patent Applications directed to positive allosteric modulators (PAMs) of the muscarinic M4 acetylcholine receptor some of which include: WO2013/126856A1 (substituted 5-aminothieno[2,3-C]pyridazine-6-carboxamide analogs); WO2014/035829A1 (substituted 3-aminothieno[2,3-C]pyridine-2-carboxaminde analogs); WO2015/027204A1 (substituted thieno[2,3-B]pyridine-2-carboxamide analogs); and WO2015/027214 (substituted thieno[2,3-C]pyridazine-6-carboxamide analogs).
WO2006/047124A1 (Lilly) discloses thienopyridines as allosteric potentiators of the M4 muscarinic receptor.
New or improved activators, including positive allosteric modulators, of the muscarinic M4 receptors are needed for providing new and improved therapies to treat M4-mediated diseases and disorders such as Schizophrenia, Alzheimer's Disease and others described herein.